Only 10 years ago, physicians could do nothing to influence the course
of MS for anyone. Nothing. They could control symptoms, and recommend therapies
to improve people’s lives, preserve some abilities, and help people learn
to compensate for losses. But the central problem—the MS—was beyond the
reach of medicine. Those days ended in 1993 with FDA approval of Betaseron.

By 1997, there were two more “disease-modifying” drugs—all with proven
ability to cool down part of the MS process. All are immune-system modulators.

A committee of MS specialists who advise the National MS Society reviewed
the evidence available in 1998. The group found the benefits of Copaxone,
Betaseron, or Avonex to be so clear that they issued the Society’s Disease
Management Consensus Statement. It strongly supports early intervention
with one of these drugs by people with relapsing-remitting MS, “to reduce
future disability and improve quality of life.” This recommendation was
made despite the fact that these drugs don’t cure MS, they don’t stop symptoms,
and they don’t help everyone equally.

Why Rebif was approved

Two trials led to FDA approval of Rebif this past March. The first,
called the PRISMS trial, was conducted at 22 centers in Europe, Canada,
and Australia. It tested an inactive placebo against two different doses
of Rebif taken three times a week for two years. All 560 trial participants
injected themselves.

The trial was “double-blinded”, meaning neither the volunteers nor the
health-care professionals knew who belonged to which group, a standard
technique to prevent bias. The results, made public in 1997, showed that
Rebif caused a statistically significant reduction in the number and frequency
of MS attacks, slowed the progression of disability, and reduced the evidence
of MS damage in the brain as revealed by MRI.

Additionally, the investigators concluded that the higher dose of Rebif
was preferable to a lower dose and that starting treatment early on rather
than later benefited patients. Following this trial, Rebif has been prescribed
to people with MS in some 60 countries around the world.

A second trial, called EVIDENCE, was sponsored by the manufacturer of
Rebif, and used a study design reviewed by the FDA. It was a “head-to-head”
test of Rebif vs. Avonex. This study was done to see if any clinical superiority
could be detected that might persuade the FDA to permit marketing Rebif
in the United States sooner than mid-2003. Since Avonex and Rebif are identical
molecules—both are interferon beta-1a—Rebif had been denied the U.S. market
under the terms of the Orphan Drug Act which protected Avonex from competition
by an identical drug for seven years.

EVIDENCE was a short-term, six-month trial, involving 677 people with
relapsing-remitting MS. Half of them injected Avonex; the other half, Rebif.
The clinical assessors were “blinded” to minimize bias, but the volunteers
knew what they were using because of the different injection schedules.

According to the FDA’ s report on the study, if the outcomes for the
two groups were different, it could rule that Rebif is a “different drug”
and thus not subject to Orphan Drug Act restrictions, even though it is
the same as Avonex at the molecular level. Similar reasoning previously
permitted the marketing of Avonex in 1996, when the nearly similar Betaseron
was already available. (Betaseron, approved in 1993, is interferon beta-1b.
The “b” refers to a structural variation in the interferon beta molecule.)

At the end of six months, Rebif showed a statistical advantage over
Avonex on all primary and secondary outcome measures, including the number
of relapses and volume of new lesions as detected by MRI. There were some
differences in side effect levels. Injection site reactions, including
pain; liver abnormalities; and drops in white blood cell counts (not, however,
associated with increases in infections), were more common in the Rebif
group.

Three experts comment

InsideMS asked three internationally known neurologists who specialize
in MS research and patient care, all members of our Medical Advisory Board,
how this development affects what they now advise their own patients.

Dr. Kenneth Johnson, who heads the Maryland Center for MS, was an investigator
in the pilot and definitive clinical trials of Betaseron and lead investigator
in the trials that led to approval of Copaxone.

“We don’t have four drugs. We have two,” he said. “Three of these are
different forms of the same thing, interferon beta. The other drug is glatiramer
acetate. The Rebif interferon is a welcome and useful addition to my clinical
practice for two reasons: first, it is the only interferon drug available
in a prefilled syringe. My patients find that very helpful. Second, Rebif
is available in two doses, which gives me more flexibility in prescribing.

“Does this mean I would switch someone who is doing well on Avonex?
Certainly not. And we follow all our MS patients very closely. We do MRIs
every 18 to 24 months as part of ongoing assessments, so we’re looking
at the silent lesion burden as well as the clinical symptoms.

“The evidence that higher interferon doses are more effective is good.
We also know higher doses produce more side effects. It’s a balancing act.
If a person can tolerate a higher dose, that’s all to the good. But we
may hear more about side effect problems with higher-dose interferons in
the coming months. We have an excellent alternative option in Copaxone.
Frankly, I consider it first for someone newly diagnosed.”

Dr. Fred Lublin, director of the Corinne Goldsmith Dickenson MS Center
at New York’s Mt. Sinai Hospital, was an investigator in the trials that
led to approval of Betaseron. He agrees with Dr. Johnson about dosing issues.

“The data supporting higher doses (referred to as ‘the dose response’)
are not perfect, but they aren’t bad, and they are certainly suggestive,”
Dr. Lublin said. “I’m telling my newly diagnosed patients that there is
now another interferon to consider. It is a higher dose, and is taken less
often than Betaseron and more often than Avonex. I want my patients to
have some choices. Convenience and ‘life style’ are still issues—but frankly
so is dosage.”

Like Dr. Johnson, Dr. Lublin would not recommend a change for anyone
who is currently doing well, regardless of which drug she or he is taking.
He is not overly worried about the “neutralizing antibodies” that a certain
percentage of people taking an interferon drug will develop. “If one of
my patients on an interferon therapy is not doing well, not responding,
I wouldn’t necessarily consider it an antibody issue. Depending on the
individual situation, I might try a higher dose or switch the patient to
Copaxone,” he said.

Dr. Richard Rudick heads the Mellen MS Center at The Cleveland Clinic,
one of the centers where Avonex was studied prior to its FDA approval.
His assessment of the antibody controversy is different.

“I was always concerned about the impact of neutralizing antibodies,
which showed up mostly in patients on Betaseron,” he said. In Dr. Rudick’s
opinion, the EVIDENCE trial shows that antibodies do affect outcome, with
Rebif offering the greatest advantages to people who remain neutralizing-antibody
negative.

“I think we will all continue to struggle with the obvious dilemma:
higher doses can be more effective, but higher doses and more frequent
injections mean more side effects. Is the difference for an individual
patient going to be big enough to make us want to do this?”

All the specialists agreed that patience is an important part of dealing
with the side effects. There are no oral formulations at this time, so
everyone needs to learn safe injection techniques. The flu-like side effects
of interferon drugs generally taper off in six months, or at about the
same time that taking the medication has become routine. Side effects of
glatiramer acetate mainly involve problems at the injection site (pain,
itching, swelling) with a possibility of a rare episode of flushing, chest
pain, and intense anxiety that passes in 30 minutes or less, leaving no
known aftereffect.

The Consensus committee originally agreed that the statistical differences
in outcomes among Copaxone, Betaseron, and Avonex clinical trials were
not sufficient in themselves to warrant recommending one of the medications
over the others. It will take several months, while the specialists review
data, before a formal supplementary statement relating to Rebif is added
to the recommendation. But the basics of the National MS Society’s Disease
Management Consensus Statement are certain to remain: The advantages of
the disease-modifying drugs are real. They represent the best available
chance to reduce future disability and improve quality of life for many
people with MS.

Cost, training, and support issues

There is one area where Rebif is different from the other three. According
to www.drugstore.com, the annual retail price of Avonex is $10,412; Betaseron
is $12,544; Copaxone is $11,280. Rebif is $13,875 a year. Retail prices
vary according to the pharmacy used, as do insurance co-pays and prescription
drug caps.

Serono (Rebif), Berlex Laboratories (Betaseron), Biogen (Avonex), and
Teva Neuroscience (Copaxone) all offer patient support programs [see Chart
of the Disease-Modifying Drugs for contact information], injection training,
information about MS, reimbursement counseling to maximize insurance coverage
or any available pharmaceutical benefit programs, plus some financial assistance
for those who are without adequate resources.

The bottom line

The most important guide through all this is a knowledgeable physician.
For information about the nearest MS clinical centers and MS specialists,
call 1-800-FIGHT-MS and select Option #1. To assist physicians and allied
healthcare professionals involved in MS care, the Society offers the Professional
Resource Center at 1-866-MS-TREAT, on our professional Web site http://www.nationalmssociety.org/PRC.asp.

After the Consensus Statement was issued, another drug gained FDA approval
for use in MS. Novantrone offers hope of modifying the course of secondary-progressive,
progressive relapsing, and rapidly worsening relapsing-remitting MS. It
is a powerful immune suppressant, which is given intravenously once every
three months, and has a lifetime dose limit to avoid the risk of injury
to the heart. It is the first new drug approved for progressive forms of
MS, but it is not in the same category as the self-injectable immune modulators
recommended for long-term use.